Low-intensity chemotherapy (mini-HCVD) and ponatinib followed by blinatumomab (blina) and ponatinib for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL): A phase II study.
Authors: Lewis Fady Nasr, Elias Jabbour, Fadi Haddad, Nicholas James Short, Walid Macaron, Cedric Christophe Nasnas, Marianne Zoghbi, Ghayas C. Issa, Musa Yilmaz, Naval Guastad Daver, Naveen Pemmaraju, Lucia Masarova, Farhad Ravandi, Nitin Jain, Wuliamatu Deen, Christopher Loiselle, Lourdes Waller, Glenda Banks, Rebecca Garris, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2023)

e19028 Background: The combination of mini-HCVD and ponatinib followed by blina and ponatinib may improve outcomes compared with HCVAD/ponatinib in patients (pts) with Ph+ ALL while reducing toxicity and the need for ASCT. Methods: Pts with newly diagnosed (ND) or relapsed/refractory (R/R) Ph+ ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Mini-HCVD alternating with methotrexate (MTX)/cytarabine were given on Cycles(C) 1-4, followed by blina/ponatinib on C5-8. Pts received ponatinib 30mg daily in C1, with dose reduction to 15mg daily once in complete molecular response (CMR). Rituximab was given for CD20+ disease. Maintenance was with ponatinib and vincristine/prednisone for 15 cycles alternating with blina/ponatinib every 3 cycles, followed by ponatinib for at least 5 years. All pts received 12 intrathecal chemotherapy injections. Results: 17 pts (11 ND, 3 R/R, 3 CML-LBP) were treated between 11/2019 and 7/2022 (Table). BCR:ABL1 transcripts were p190 in 7 (64%) pts in the ND cohort. In the ND cohort, 4 (36%) pts had BCR:ABL1 in myeloid cells by FISH and 1 (9%) had a small population of myeloid blasts, suggesting a myeloid component. None of the pts with CML-LBP had received prior therapy. All evaluable pts achieved CR. Among evaluable pts in the ND, R/R, and CML-LBP cohorts, CMR was achieved in 6/8 (75%), 2/2 (100%), and 2/3 (67%) pts, respectively. 2 of the 5 ND pts who had evidence of myeloid involvement did not achieve CMR (1 had negative MRD by NGS). With a median follow-up of 28 months (range, 6-37), the 2-year continuous remission duration and OS rates were 93% and 82% in the entire cohort, and 90% and 82% in the ND cohort, respectively. In the ND cohort, 1 (9%) pt had isolated CNS relapse, 3 (27%) pts died (2 in CR due to COVID-19 and 1 of ASCT complications), and 7 (64%) pts are in remission without ASCT. No pts relapsed in the R/R cohort, 1 pt underwent ASCT, 1 pt died in CR from MTX-associated disseminated necrotizing leukoencephalopathy, and 1 pt is in remission without ASCT. None of the CML-LBP relapsed; 1 pt underwent ASCT in CR. Ponatinib dose was reduced in 2 pts prior to obtaining CMR (1 pancreatitis, 1 cardiomyopathy). One pt switched from ponatinib to dasatinib due to pulmonary embolism in C2. No pts required dose modification of blina. The 60-day mortality rate was 0%. Conclusions: In Ph+ ALL, the sequential combination of mini-HCVD/ponatinib followed by blina/ponatinib resulted in high rates of CMR, encouraging survival, and had an acceptable safety profile. Clinical trial information: NCT03147612 . [Table: see text]